Enhancing aged CD4 cognate function with cytokines. Immunization of the elderly is critically important since it can reduce the morbidity associated with infectious disease seen in the aged. The problem is that vaccine efficacy can be decreased 60 to 70% in the aged. This is extremely important since elderly persons exhibit a much increased risk of hospitalization and death from infectious diseases, such as influenza, compared to younger persons. We have used a T cell receptor transgenic (TCR Tg) model to examine how age affects CD4 function. The advantage of TCR Tg models is that they allow us to directly compare the in vitro and in vivo function of homogenous populations of antigen-specific CD4 cells from young and aged mice. By using these models, we can eliminate some of the differences in young and aged populations, such as the proportion of memory to naive cells that increases with age. In preliminary studies, we have shown that naive Tg CD4 cells from aged mice produce less IL-2 upon in vitro TCR stimulation compared to young cells. This has a profound impact on the initial expansion of naive aged cells and on subsequent differentiation of effectors. Furthermore, we have shown that these aged defects in expansion and cytokine production also occur in vivo in an adoptive transfer model. In vivo, decreased CD4 function due to aging could potentially impact both B cell and CTL responses. In fact, our studies show that there is a profound defect in the cognate helper function of aged CD4 cells. The goal of this grant proposal is to determine if exogenous cytokines or adjuvants can improve the function of aged CD4 T cells. We have determined that the aged CD4 defect in expansion and IL-2 production is overcome by immunization with adjuvants that induce inflammatory cytokines or by the cytokines themselves. In this grant, we will examine the effects of these cytokines on the in vitro and in vivo function of aged CD4 cells. We will examine how cytokines can act to enhance IL-2 production by aged CD4 cells in vitro. We will l also determine if cytokines or adjuvants can improve cognate helper function--including the impact on antigen-specific antibody production and induction of protective antibodies, as well as cognate help for CD8 responses. These studies will provide us with valuable information on how to improve the in vivo function of antigen-specific CD4 cells in the aged.